E!10611 A Clinical Candidate for the Treatment of Rheumatoid Arthritis

Autoimmune diseases are conditions when the body's defence mechanism are attacking itself and destroying tissue. These diseases are alongside cancer and cardiovascular disease the most common causes of disease in the world today. Rheumatoid arthritis (RA) is an autoimmune disease affecting about 1% of the world's population and three in four RA patients are female. RA is a lifelong condition associated white blood cells (immune cells) that attack and destroy tissue in affected joints. Early detection and aggressive therapy have proven crucial in order to successfully treat and dampen symptoms of RA. Still, a significant proportion of people living with RA experience a lack of effective treatment options. Effective treatment for RA requires a drug that can decrease the diseased activities of white blood cells and inflammation without unacceptable side effects. The main goal of our project is to develop a new drug that can reduce the burden of RA while limiting side effects and offer treatment to those patients who have been non-responsive to existing therapies or where therapies have lost their effect. Restricting cell metabolism, the mechanisms controlling energy, has been shown to prevent immune cell activity, activity that is central both in disease initiation and in progression. Rheumatech will in this project develop, test and optimize drugs to be ready for human clinical testing. During the project period, the consortium partners have collected valuable results crucial for the successful completion of the project. For the main participant, Rheumatech, has focused on the development of chemical compounds for preclinical testing in animal models. Mainly this work has consisted of developing active compounds. The development has been complicated and Rheumatech has reached a phase where compounds can be introduced to biological models. As the compounds now is in the preclinical phase, the participant CTC has for regulatory reasons not initiated testing of Rheumatechs compounds in humans. This, despite that CTC has developed and are in the process of testing other medicines in their clinical model. Rheumatech see testing of their compounds in CTCs klinical model as a major focus in their future effort to develop medicines targeting RA.

I prosjektperioden har partnerne samlet verdifull informasjon for en vellykket ferdigstilling av prosjektet. Rheumatech har utviklet kjemiske stoffer som kan testes i biologiske modeller. Rheumatechs arbeid har i all hovedsak bestått i å utvikle kjemiske stoffer som hemmer nøkkelenzymer i energimetabolismen i hvite blodceller fra pasienter med autoimmun sykdom. Arbeidet har vært komplisert av at enkelte kjemiske stoffer har en giftig effekt på immunceller og at de derfor ikke er egnet for testing i dyremodeller. Rheumatech har løst dette ved å identifisere nye og alternative stoffer som når syntetiseres og testes i biokjemiske og biologiske modeller. Stoffene befinner seg nå i preklinisk fase. Partneren CTC har derfor ikke testet Rheumatecks stoffer i deres kliniske modellen som de har utviklet i løpet av prosjektperioden. CTC tester andre medikamenter og Rheumatech ser at CTC vil være en naturlig partner å henvende seg til når Rheumatechs stoffer er godkjent i prekliniske modeller.

A significant proportion of people living with RA experience a lack of effective treatment options. Rheumatech's goal is to develop and bring to market a first-in-class drug for the treatment of these patients and thereby improve their quality of life. Our candidate compounds are small organic molecules inhibiting lactate dehydrogenase (LDH) isoforms, which decrease the ability of T cells to proliferate and produce biochemical messengers that are instrumental for disease propagation. Effective treatment for RA requires a drug that can decrease the pathogenic activities of harmful T cells and limit inflammation without provoking unacceptable side effects. In a direct approach to connect molecular research to patient care, the main goal of our project is to develop a new drug that can reduce the burden of RA while limiting unwanted side effects and also treating those patients who have been non-responsive to anti-Tumour Necrosis Factor alpha (TNF) therapy or lost their responsiveness to this form of therapy. Activated lymphocytes require large amounts of energy, mostly generated from the nutrient glucose. Restricting the supply of glucose through glucose deprivation or inhibiting its combustion has been shown to prevent lymphocyte activity, activity that is central both in disease initiation and progression. Through medicinal chemistry, animal toxicity testing and pre-clinical planning up-to phase I initiation; we aim to identify our lead candidate and make it ready for first-in-human clinical trials.